雷美替胺(Ramelteon)详细说明书

Ramelteon is a selective MT1/MT2 melatonin receptor agonist developed by Takeda Pharmaceuticals of Japan. It was first approved by the US FDA in July 2005. In 2007, the US FDA issued an important safety warning for sedative-hypnotic drugs including this drug, requiring drug manufacturers to update drug labels to add risk warnings for severe allergic reactions and complex sleep behaviors such as "sleep driving". It also stipulated that warning letters must be sent to medical professionals and detailed medication guidance must be provided to patients.

1. Indications

Insomnia

Ramelteon is suitable for the treatment of insomnia characterized by difficulty falling asleep.

2. Usage and Dosage

1. Adult dosage

The recommended dose of Ramelteon is 8 mg taken within 30 minutes before going to bed. It is not recommended to take it with or immediately after a high-fat meal. The total daily dose should not exceed 8 mg.

2. Medication for patients with hepatic insufficiency

Ramelteon is not recommended for patients with severe hepatic insufficiency. Ramelteon should be used with caution in patients with moderate hepatic impairment.

3. Combination with other drugs

Ramelteon should not be used in combination with fluvoxamine. Ramelteon should be used with caution in patients taking other drugs that inhibit CYP1A2.

Recommended articles:

3. Specifications and properties

Ramelteon is an oral tablet with a specification of 8 mg/tablet. The 8 mg tablet is round in shape and covered with a light orange-yellow film coating. The word "TAK" is printed on one side of the tablet and the "RAM-8" logo is printed on the other side.

IV. Adverse reactions

Common adverse reactions

Headache, drowsiness, dizziness, fatigue, nausea, worsening of insomnia, upper respiratory tract infection, diarrhea, myalgia, depression, taste disorder, joint pain.

Recommended articles:

5. Precautions

1. Severe allergic reactions and anaphylactoid reactions

It is reported that rare cases of angioedema involving the tongue, glottis or larynx occur in patients after taking the first or subsequent doses of Ramelteon. Some patients also experience other symptoms, such as difficulty breathing, closing of the throat, or nausea and vomiting, suggestive of an allergic reaction. Some patients require medication in the emergency department. If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after receiving Ramelteon should not use this drug again.

2. Diagnosis of comorbidities needs to be assessed

Because sleep disturbance may be the first manifestation of physical and/or psychiatric illness, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient. Failure to resolve insomnia after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical disorder and should be evaluated. Worsening insomnia or the development of new cognitive or behavioral abnormalities may be the result of unrecognized underlying psychiatric or physical illness and require further evaluation of the patient. Increased insomnia and the development of cognitive and behavioral abnormalities were observed with ramelteon during the clinical development program.

3. Abnormal thinking and behavioral changes

Research shows that the use of hypnotics may cause a variety of cognitive and behavioral abnormalities. In patients with depression, hypnotics may exacerbate depressive symptoms (including suicidal tendencies). Be particularly vigilant when using ramelteon, as it may induce neuropsychiatric symptoms such as hallucinations, abnormal behaviors (such as restlessness, mania), amnesia, and anxiety. What deserves more attention is complex behaviors such as "sleep driving" (such as unconscious eating, talking or having sex). These behaviors are often accompanied by memory loss, and the combination with alcohol or other central depressants will significantly increase the risk. This may occur regardless of whether the patient has a history of hypnotic drug use. Once such symptoms occur, discontinuation of ramelteon should be considered immediately.

4. Central nervous system effects

After taking ramelteon, patients should avoid engaging in hazardous activities that require concentration (such as operating motor vehicles or heavy machinery). After taking ramelteon, patients should limit activities to those necessary to prepare for sleep. Patients should be advised not to consume alcohol concurrently with ramelteon as alcohol and ramelteon may have additive effects when used together.

5. Reproductive effects

Ramelteon is associated with effects on adult reproductive hormones, such as reduced testosterone levels and increased prolactin levels. It is unclear what effects long-term or even long-term intermittent use of ramelteon might have on the developing human reproductive axis.

6. For patients with comorbid diseases

Ramelteon has not been studied in subjects with severe sleep apnea, so its use in this population is not recommended.

7. Laboratory abnormalities

For patients with unexplained amenorrhea, galactorrhea, decline, or fertility problems, evaluation of prolactin and testosterone levels should be considered as appropriate. It is not known that ramelteon will interfere with commonly used clinical laboratory tests. Additionally, in vitro data indicate that ramelteon does not cause false-positive results for benzodiazepines, opioids, barbiturates, cocaine, cannabinoids, or amphetamines in two standard in vitro urine drug screening methods.

6. Contraindications

Patients who develop angioedema after treatment with ramelteon should not use this drug again. Patients should not take ramelteon with fluvoxamine

VII. Drug interactions

1. Effects of other drugs on ramelteon

(1) CYP1A2 inhibitors

Potential pharmacokinetic interactions (significant increase in serum ramelteon concentration). Avoid concurrent use with strong CYP1A2 inhibitors; use caution if used concurrently with less potent CYP1A2 inhibitors.

(2) CYP3A4 and CYP2C9 inhibitors

Potential pharmacokinetic interactions (increased serum concentrations of ramelteon and active metabolites). Use caution if used concurrently with strong inhibitors of CYP3A4 or CYP2C9.

(3) CYP isoenzyme inducers

Potential pharmacokinetic interactions (decreased serum concentrations of ramelteon and active metabolites). The efficacy of ramelteon may be reduced when used concomitantly with strong CYP inducers.

2. Effect of alcohol on ramelteon

Alcohol itself can impair performance and cause drowsiness. Because the intended effect of ramelteon is to promote sleep, patients should be reminded not to drink alcohol while taking ramelteon. Combining products may have additive effects.

3. Drug/Laboratory Test Interactions

It is not known that ramelteon will interfere with commonly used clinical laboratory tests. Additionally, in vitro data indicate that ramelteon does not cause false-positive results for benzodiazepines, opioids, barbiturates, cocaine, cannabinoids, or amphetamines in two standard in vitro urine drug screening methods.

8. Medication in Special Populations

1. Pregnancy

Available data from post-marketing reports on the use of ramelteon in pregnant women have not determined drug-related risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Use only when the benefits of treatment outweigh the potential risks. Animal experiments (150mg/kg/day and above) show that ramelteon may cause fetal diaphragm hernia, skeletal variation and other teratogenic effects.

2. Lactation period

There are no data on the presence of ramelteon or its metabolites in breast milk, the effects on breastfed infants, or the effects on milk production. Ramelteon and/or its metabolites are present in rat milk. When a drug is present in animal milk, it is likely that the drug is present in human milk. Due to the mechanism of action of ramelteon, there is a potential risk of drowsiness in breastfed infants. The developmental and health benefits of breastfeeding should be considered, as well as the mother's clinical need for ramelteon and any potential adverse effects of ramelteon or the underlying maternal condition on the breastfed infant.

3. Use by children

The safety and effectiveness of ramelteon in pediatric patients have not been established. Further research is needed before it can be determined that this product is safe for use in prepubertal and adolescent patients.

4. Use by the elderly

No overall difference in safety or effectiveness was observed between elderly subjects aged 75 or above, and young adult subjects.

5. Chronic obstructive pulmonary disease

There is no available information on the effects of multiple doses of ramelteon on the respiratory system in patients with COPD. Respiratory depression in patients with COPD cannot be clearly understood.

6. Sleep apnea

There is no information available on the effects of multiple doses of ramelteon on breathing in patients with sleep apnea. The impact of exacerbations in patients with mild to moderate sleep apnea cannot be known with certainty.

7. Hepatic Impairment

The exposure of subjects with mild hepatic impairment to ramelteon increased fourfold, and the exposure of subjects with moderate hepatic impairment increased more than tenfold. Ramelteon should be used with caution in patients with moderate hepatic impairment. Ramelteon is not recommended for use in patients with severe hepatic impairment.

8. Renal function impairment

Studies have shown that after patients with renal insufficiency take ramelteon, the Cmax (peak concentration) and AUC0-t (area under the plasma concentration-time curve) of the prototype drug and metabolite M-II are not affected. Therefore, patients with renal insufficiency do not need to adjust the dosage of ramelteon.

9. Overdose

General symptomatic and supportive measures should be taken, and gastric lavage should be performed immediately when appropriate. Intravenous fluids should be administered as needed. As in all overdose cases, breathing, pulse, blood pressure, and other appropriate vital signs should be monitored, and general supportive measures should be taken. Hemodialysis is not effective in reducing exposure to ramelteon. Therefore, the use of dialysis to treat overdose is inappropriate.

10. Validity period

36 months.

11. Storage conditions

Ramelteon is stored at 25°C; it is allowed to shift to 15° to 30°C. Keep the container tightly closed and protected from moisture and moisture.

12. Pharmacokinetics

1. Absorption‌

It is absorbed rapidly after oral administration, with the peak time being about 0.75 hours (0.5-1.5 hours). The absolute oral bioavailability is low (1.8%), mainly due to significant first-pass metabolism.

2. Distribution‌

The serum protein binding rate is about 82% (mainly bound to albumin). The distribution volume is large (73.6L), suggesting widespread tissue distribution.

3. Metabolism‌

Mainly through CYP1A2 oxidative metabolism (minorly involving CYP2C/3A4), it generates hydroxyl/carbonyl derivatives and glucuronic acid conjugates. Exposure to the main active metabolite M-II was 20-100 times higher than that of the parent drug.

4. Elimination‌

84% is excreted in urine, 4% is excreted in feces, and the prototype drug is excreted very little (<0.1%). The half-life is short (1-2.6 hours for prototype; 2-5 hours for M-II), and there is no significant accumulation after daily administration. It was basically completely eliminated within 96 hours, and the plasma concentration dropped below the detection limit after 24 hours.